Azacitidine and luspatercept metronomic therapy for intermediate- to high-risk myelodysplastic syndrome: A prospective single-center phase II clinical trial

Abstract Introduction: Although hypomethylating agents (HMA) have improved outcomes in higher-risk myelodysplastic syndromes (MDS), survival remains poor, particularly for transplant ineligible patients. Anemia is a hallmark of MDS. Symptomatic anemia is associated with complications such as cardiovascular events, increased fall and fracture risk, which significantly reduced quality of life and overall survival. In contrast with continuous azacitidine administration which carries higher risks of myelosuppression and infection, metronomic HMA chemotherapy results in milder myelosuppression, reduces the risk of infection, and improves treatment convenience for patients with obvious cytopenia. Luspatercept has demonstrated efficacy and safety in lower-risk MDS while its role in non-low-risk MDS is yet to be established. Therefore, this study aimed to evaluate the safety, tolerability, and efficacy of metrononic azacitidine combined with luspatercept in intermediate- to high-risk MDS. Methods: We conducted a prospective, single-center, single-arm phase II clinical trial. Adult patients with intermediate- to high-risk MDS (IPSS-R>3) were enrolled. Azacitidine 75 mg/m2/day administered subcutaneously twice weekly for the first three weeks of each 28-day cycle, and luspatercept (1mg/kg subcutaneously) injected on the first day of the fourth week. Responses were assessed using modified 2006 International Working Group (IWG) criteria. Adverse events (AEs) were graded per CTCAE v5.0. Results: Between July 2023 and July 2025, 24 patients were enrolled. Median follow-up was 3 months (range: 1-24 months). The median age was 71 years (range: 48-83). Baseline laboratory parameters were as follows: absolute neutrophil count 0.92x10⁹/L (range: 0.54-1.62), hemoglobin 65g/L (range: 50-89), and platelet count 72x10⁹/L (range: 4-341). Nineteen patients (79%) were transfusion dependent (TD) at baseline. Median bone marrow blast percentage was 4% (range: 0-10). By IPSS-R, patients were classified as intermediate-risk (n=10), high-risk (n=5), or very high-risk (n=9) groups. By IPSS-M, patients were classified as moderate low risk (n=1), moderate high risk (n=6), high risk (n=6) or very high risk (n=11) groups. Thirteen patients (54%) had grade 1-3 myelofibrosis. Cytogenetical and molecular characteristics included: complex karyotype (n=4), TP53 mutation (n=4), ASXL1 mutation (n=4), DNMT3A mutation (n=2), TET2 mutation (n=3), and SF3B1 mutation (n=6). Patients received a median of 4 treatment cycles (range: 1-14). The overall response rate (ORR) was 67% (16/24), including a complete remission (CR) rate of 21% (n=5). ORR and CR rates showed no statistically significant difference between the myelofibrosis and non-myelofibrosis subgroups. Median time to first response was 1 month (range: 1-3). Additionally, 6 out of 19 TD patients (32%) achieved transfusion independence. Two patients (8%) progressed to AML after 8 and 12 months. For the safety profile, no grade 4 myelosuppresion was documented with only transient neutropenia seen after the HMA treatment. Only 1 death occurred due to pulmonary infection associated respiratory failure. Conclusions: Metronomic therapy with azacitidine combined with luspatercept appears to be an effective and safe approach for intermediate- to high-risk MDS patients. Patients with myelofibrosis can also benefit from this regimen.